13
Jan2009

Posted by Amy Davis, program director

Last year the U.S. Food and Drug Administration (FDA) ended the need for clinical trials conducted outside of the U.S. to comply with the Declaration of Helsinki (DOH). Now, such research must be conducted in accordance with Good Clinical Practices (GCP) of the International Conference on Harmonization.

Critics of this change describe it as a "major victory of corporate interests" since it arguably weakens the ethical standards for international clinical trials, making it easier to conduct research outside the US than inside. An additional criticism is that the change creates new inconsistencies among international policies related to human subjects research and puts further out of reach the universal goal for a harmonious, global system of regulation of biomedical research. Many countries rely on the Declaration of Helsinki as a basis for their research policies. Allowing US companies to conduct research in those countries, that is not compliant with this document, creates inconsistent ethical standards for the research conducted there.

Critics of the revised FDA regulations also highlight several differences between the DOH and the GCP. They say the GCP principles allow placebo-controlled clinical trials, while the DOH requires new drugs to be tested against “the best current prophylactic, diagnostic, and therapeutic method.” They also point out that the GCP does not address conflicts of interest, the need to publish results, or the tested drug’s post-trial availability to research subjects.

However, the FDA justifies the change because the GCP principles provide more specific guidance on how to design research trials, monitor safety, and report adverse events, all of which ultimately offer greater protections for human subjects.

Most of us who work in the field of human subjects research are aware of the importance of the DOH as a foundational policy for the ethical conduct of biomedical research. Inspired in part by the horror of the Nazi experiments revealed during the Nuremberg Trials, the DOH was developed and adopted by the World Health Association in 1964. The document has been revised (most recently in November 2008) six times since its first adoption to keep up with technological advances and scientific discovery, but remains the most widely used set of ethical principles that guide the protection of human subjects in biomedical and social research. The DOH is cited in research policies adopted throughout the world, and many scholarly journals prohibit the publication of papers based on research that was not conducted in compliance with the DOH.

So we wonder:

Do you think the revised FDA regulations allow U.S. sponsors to conduct research more easily outside the U.S. than inside?

If so, does this lead to the unjust treatment of research subjects?

Are the GCP standards sufficient and appropriate for the protection of human subjects in research?

How important is the harmonization of ethical principles in the conduct of international research?

Let us know your thoughts either on this blog or through our discussion forums (members only).

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11 thoughts on “FDA Selects GCP Over DOH for Research Conducted Outside U.S.

  1. Brad Noren

    I am not surprised that the US Food and Drug Administration (FDA) has adopted the standards outlined in the International Committee on Harmonization document “E6 Good Clinical Practice: Consolidated Guidance” (GCP) for determining the acceptability of non-IND foreign clinical studies.

    As noted above, the previous FDA standard was the Declaration of Helsinki (DOH), issued and maintained by the World Medical Association. This document has its place in the Parthenon of Ethical Declarations, alongside the Nuremberg Code and the Belmont Report. It is a remarkable statement of PRINCIPLES that should continue to influence the way we think about the conduct of medical research involving human subjects. But as a REGULATORY STANDRD for the performance of non-IND foreign clinical studies, it falls short in at least two aspects.

    First, I argue that effective regulations are those which are easy to understand. Non-compliance should be readily identifiable and compliance should be irrefutable. The vague and imprecise statements contained in the DOH do not provide the protection of clarity. Phrases like “should consider”, “appropriate caution”, “careful assessment”, “reasonable likelihood”, “every precaution”, and “extreme care” are just examples. Think of it this way. Would the guy sent to defuse the bomb appreciate a field manual that reads, “After careful consideration and consultation with all appropriate stakeholders, extreme caution should be exercised so as to cut the wire most likely to defuse the bomb”? No! Give him a field manual that says, “Cut the RED wire”. GCP provides clear(er) guidelines for the conduct of non-IND foreign clinical studies.

    Second, The DOH is beyond the reach of FDA policy makers. Allowing a non-governmental entity free reign to write the standards by which the government manages an industry is not optimal. Imagine the outrage if the oil industry were allowed to write its own regulations (okay, perhaps that’s not a good example). My point is that the regulators should control, or have significant power of influence over, the standards that they are responsible for enforcing. In my mind, FDA is justified in adopting GCP as this standard.

    While not perfect, and certainly not as ambitions or high-minded as the DOH, GCP offers a clear floor – a baseline, above which any country is free to set its own standards for the conduct of clinical studies involving human subjects. FDA made the right call.

    (The opinions expressed herein are the product of a slow Friday afternoon at the office and subject to change should I be asked to defend them during my next job interview.)

    Brad Noren

    Reply
  2. Anonymous

    Thanks, Brad, for the great post. I certainly agree with you that clearly written regulations are more effective than unclear ones. But what do you say to the notion that the protection of human subjects is nothing like diffusing a bomb in that it requires subjectivity based on sound judgment and “high-minded” ethical principles? And if, as you say, “any country is free to set its own standards for the conduct of clinical studies involving human subjects” might it be objectionable for the U.S. to lower its standards? (The opinions expressed herein are influenced by the inspirational vibes coming from our nation’s capitol this morning!)

    Reply
  3. Brad Noren

    Anonymous,

    I can’t speak for the FDA, but I would imagine that as a regulatory authority, rather than a moral or ethical authority, the agency will have an easier time determining whether non-IND foreign studies were conducted appropriately if their standards are more objective than subjective. Remember, this is only about whether data collected in overseas trials can be considered as part of a US marketing application.

    On the second point, the US hasn’t lowered its standards. In fact, they’ve been strengthened through increased clarity and enforceability. In addition, allowing placebo-controlled studies (previously restricted under DOH) will likely reduce the number of human subjects that must be exposed to risk in the name of evaluating the safety and efficacy of any given agent.

    Brad Noren

    Reply
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